N-substituted-n-alkanol piperazine carbamates and acid addition salts thereof

ABSTRACT

N-SUBSTITUTED-N&#39;&#39;-ALKANOL PIPERAZINE CARBAMATES OF THE GENERAL FORMULA I   1-R,4-(R2-N(-R3)-COO-CH(-R1)-(CH2)N-)PIPERAZINE   WHEREIN R, R1, R2, R3 AND N ARE AS DEFINED IN THE SPECIFICATION, THE ACID ADDITION SALTS OF THESE CARBAMATES, A METHOD OF MANUFACTURING SAME FROM AN ALCOHOL OF THE GENERAL FORMULA II   1-R,4-(HO-CH(-R1)-(CH2)N-)PIPERAZINE   AND THERAPEUTIC COMPOSITIONS CONTAINING THE CARBAMATES AND SALTS THEREOF, HAVING NEUROLEPTIC, TRANQUILIZING AND CENTRAL ANALGESIC PROPERTIES.

United States Patent US. Cl. 260268 FT 2 Claims ABSTRACT OF THE DISCLOSURE N-substituted-N-alkauol piperazine carbamates of the General Formula I R; Rs (I) wherein R, R R R and n are as defined in the specification, the acid addition salts of these carbamates, a method of manufacturing same from an alcohol of the General Formula II B1 and therapeutic compositions containing the carbamates and salts thereof, having neuroleptic, tranquilizing and central analgesic properties.

This invention relates to 1,4-disubstituted piperazine derivatives which are non-symmetrical, and more particularly to N-substituted-N -alkanol-piperazine carbamates, the acid addition salts thereof, and to a method of manufacturing same. The invention also provides pharmaceutical preparations containing the said carbamates and salts thereof.

The derivatives of the invention have the General Formula I:

where R R R are each independently selected from hydrogen atoms, halogen atoms, nitro groups, lower alkyl groups, lower alkoxy groups, and acetyl, propionyl and oxo-alkyl groups, and n represents 2 or 3; (b) aand p-naphthyloxyalkyl groups of the formulae and n being 2 or 3; (c) aroylalkyl groups of the formula 0 where R is selected from hydrogen and halogen atoms and lower alkoxy groups and n" is 2, 3 or 4;

(d) thienoyl alkyl groups of the formula where n" is 2, 3 or 4; and (e) the dimethyl-amino-ethyl group N-CHr-CHP C s (2) n is 1 or 2; I (3) R is selected from a hydrogen atom (with the proviso that n is then 1 or 2) and alkyl and aryl groups, n

' then being 1 in both cases; and

(4) R and R are each independently selected from hydrogen atoms, lower alkyl and lower halogenoalkyl groups, phenyl, halogenophenyl, alkoxyphenyl, polyalkoxyphenyl, trifluoromethylphenyl, nitrophenyl, and alkylphenyl groups, benzyl, cyclohexyl and naphthyl groups, cyclic groups containing the adjacent: nitrogen atom in their ring, such as pyrrolodine, piperidine, and morpholine, either substituted or unsubstituted, and sulfonamide, benzene-sulfonyl, para-toluenesulfonyl, naphthalene sulfonyl, and xylene sulfonyl groups; provided that (1) when R is a hydrogen atom and IR is the radical where R, is as defined with the exclusion of hydrogen, and n" is 3 or 4, then R and R are not hydrogen or identical lower alkyl groups; and

(2) when R is the radical R and R are not hydrogen atoms, nor identical lower alkyl groups, nor unsubstituted aryl. groups, nor aryl groups substituted by an alkoxy, alkyl or halogenoalkyl group.

The present invention also provides the acid addition salts of the carbamates of General Formula I, with organic or non-toxic mineral acids; these salts are pharmaceutically acceptable and have the additional advantage of being soluble in water.

The present invention further provides pharmaceutical preparations containing one or more of the carbamates and/or their salts as the active ingredient. These pharmaceutical preparations are intended for administration orally rectally, parenterally or locally by means of simple tablets or pills, coated or not with a view to enteric splitting or retardation; capsules, gelatinates, suppositories, ampoules which can be swallowed in water or injected, creams, lotions, and ointments: all these are prepared according to standard practice with the excipients corresponding to the forms chosen.

The carbamates and salts thereof described above are useful compounds from the pharmacological point of view because of the fact that they possess remarkable neuroleptic, tranquilizing and central analgesic properties. To these properties are also added, for certain derivatives, anti-inflammatory, hypertensive, anti-histamine and antipyretic properties.

The carbamates of the present invention are prepared from N-substituted-N'-alkanol-piperazines of the General Formula II:

This reaction is carried out in a solvent such as methylcellosolve, at boiling temperature, and in the presence of an alkaline substance, e.g. sodium carbonate. ';-.,Thecarbamates of the present invention are obtained by.startingfromcompounds of the General Formula II in accordance with the following procedures:

(a) WhnR, and R both' represent a hydrogen atom the compounds ofthe General'Formula H are obtained in accordance'with the reaction:

R1 R, n and R being as defined above.

The transesterification of ethyl carbamate by the hydroxylated compound of General Formula II is preferably carried out in anhydrous toluene in the presence of tri(isopropyloxy)aluminum.

(b) When R (or R represents a hydrogen atom, and

R (or R a lower alkyl, halogenoalkyl, phenyl, halophenyl, nitrophenyl, alkylphenyl, naphthyl, cyclohexyl, sulfonamide, benzene sulfonyl, para-toluene sulfonyl, naphthalene sulfonyl or xylene sulfonyl group, the carbamates of the General Formula I are obtained in ac cordance with:

R,n and R being as defined above.

5 The reaction is then preferably carried out in .an appropriate organic solvent such as benzene, toluene, or xylene in the presence of an alkaline agent such as triethylamine.ortriethylenediamine. The reaction is preferablycarried out. at a temperature lying between the ambient temperature and the boiling point of the reaction medium, Y a

The isocyanates of theGeneral Formula III are products fknown themselves and can be obtained from the appropriate azides. These latter are transformed by the classic Curtius reaction into isocyanates by heating in benzene or otherinert solvent; the isocyanates may be reacted with thealcohol of the General Formula II without there'being any necessity to isolate them.

(or i (or RI) R2) (c) When R and R identical or not, each are lower alkyl group or phenyl, halogenophenyl, alkylphenyl, alkoxyphenyl, benzyl, cyclohexyl, or naphthyl group, or together form a ring with the adjacent nitrogen atom, such as pyrrolidine, piperidine, or morpholine group, the carbamates of the General Formula I are obtained in accordance with:

R, R and n being as defiined above.

When R and R each represent a lower alkyl group it is preferred, bearing in mind the results of the reaction, to operate in a polar solvent such as dioxan in the presence of an alkaline agent capable of combining with the hydrochloric acid formed in the course of the reaction, such an agent being sodium carbonate or triethyl amine.

When R and R are other of the groups indicated above the reaction is preferably carried out in an appropriate solvent such as benzene, toluene or xylene in the presence of an excess of the alcohol of the General Formula II in order to fix the hydrochloric acid liberated in the course of the reaction.

In both cases the reaction is preferably effected at the boiling temperature of the solvent being utilized.

The carbamates thus prepared exist in their free form or may be isolated in the form of salts with the aid of inorganic or organic acids by using standard methods for the preparation of salts.

The following examples are given in order to illustrate the invention in greater detail.

EXAMPLE I Dimaleate of N-(fl-naphthoxy)-2-ethyl-N(carbamoyloxy- 2-ethyl)-piperazine (No. 1)

A mixture of 5.34 g. (0.06 mole) of ethyl carbamate, 12 g. (0.04 mole) of N-(fi-naphthoxy)-2-ethyl-N'-(hydroxy-2-ethyl)-piperazine and 30 ml. of toluene was refiuxed in a 100 ml. balloon-flask with a 40 cm. filling column fitted with a column head for total reflux. After collecting the toluene-water azeotrope (P.E.=84 C.), the heating was stopped. 1.25 g. (0.006 mole) of tri(is0- propyloxy)aluminium was added to the reaction mixture and once again the mixture was refluxed.

The fraction distilling at 76 C. formed by the toluene-ethanol azeotrope (ethanol: 68%) was collected. After heating for 24 hours, when the'reaction was considered complete anhydrous acetone was added and the resulting mixture was filtered. After evaporation of the solvent from the filtrate an oily residue was obtained.

This was dissolved in 250 ml. of acetone, with heating.

To this solution was added a boiling solution of 11 g. of

. maleic acid in acetone. The dimaleate separated immediately by precipitation.

By recrystallization from alcohol at a product which was slightly soluble in water was obtained.

By operating under these conditions, the following typical compounds, whose physical characteristics are given in Table I, were obtained.

N [(B-naphthoxy)-2-ethyl]-N-(carbamoyloxy-2=ethyl) piperazine (No. 2).By transesterification of ethyl carbamate and N [(fl-naphthoxy)-2-ethyl]-N'-(hydroxy-2-ethyl)piperazine. The dimaleate was recrystallized from alcohol at 95.

3,810,897 6 N [(para-propionyl phenoxy) 2 ethyl]-N'- (carbamoyl- EXAMPLE III yn-p p Y transesteflfieallon Dihydrochloride of N-[y-(Z-thienoyl)-propyl]-N-(cycloof ethyl Calbamale and -[(P 'P 'P Y p fihexyl carbamoyloxy)-2-ethyl] piperazine (No. 8) 2-ethyl]-N'-(hydroxy-Z-ethyl)-piperazine. The dimale- A mixture f 113 g. (Q04 m of 2 i ate was recrystallized twice from alcohol at 95 5 enoyl)-pro yl]-N-(hydroxy-2-ethyl) piperazine and g.

1 TABLE 1 r)l.-CH-o-C0N Rl R:

Elementary analysis, percent Calculated Found Yield, No. R 1: R1 Rr=R| percent Salt F. C H N C H N i O-(CH|)| 3 1 H H 40 204K404 189 53.63 5.02 7.22 53.43 6.10 6.92

CHr-CHg-CO O-(CH:)

EXAMPLE II (0.12 mole) of cyclohexyl isocyanate was refluxed in 50 Dihydrocmoridc of ml. of anhydrous benzenetor 5 hours in the presence of {phcnyl carbamoyloxy) 2 ethy1] piperazine 4 0.77 g. of methylene dlamlne.

After coolin the solution was filtered, and the sol- A mlxture of (0'06 mole) of f vent was evapofated under reduced pressure. A crystalline benzoyl) PrOPYU'N '(hydroxyfz'fithyl) piperazlqe i product was obtained which was converted to the dihydro- (0'06 mole) of Phenyl was boned m chloride by the action of gaseous hydrochloric acid. Re- 70 of anhydrous benzene e 12 hours the Presence 0 crystallization was from a mixture of absolute alcohol of a few drops of triethylamlne. After removal of the and ethen benzene an oily P (thefl'ee base) was f Operating under these general conditions, the follow The pl'oduet e Isolated the of dlhydm ing typical compounds as listed in Table III were obchloride by dissolving the base in a mixture of acetone mined and anhydrous ether (1:1) and by bubbling a stream 0f (a) N-[(par P enoxy) 2 ethyl]-N'-[(isoprodry gaseous HCl through the solution. Recrystallization pyl carbamoy1oxy) 2 ethy1] piperazine (NO. was fromeleohel at 2 action of N-[ (para-fluorophenoxy)-2-ethyl]-N'-(hydroxy- Followmg e mode of operetlonr e follqwmg Prod Z-ethyl) piperazine with isopropyl isocyanate. The dihynets whose Physleal charactel'lstles are hsted Table II drochloride was recrystallized from a mixture of absolute were d- 40 alcohol and ether.

(*0 y lm- Y '-[(p y e (b) N-[ -(fluoro 4 e benzoyl)-propyl]-N-[(ethyl carlfil p Y the actlon bamoyloxy)-ethyl] piperazine (No. lO').--By reaction of -lfil y )-gy ly y 2 y P N-[v-(fiuoro-4-benzoyl)-propyl]-N'-(hydroxy 2 ethyl) P and Phenyl lsocyal'late- The tnmaleate was piperazine with ethyl isocyanate. The dimaleate was recrystallized from 95 alcohol- 1 crystallized from alcohol.

-[7- 4 Y )-P PY 3 (c) N-[ -(fluoro-4 benzoyl)-propyl]-N-[(cyclohexyl 'P Y Y) 2 y Plperalllle Y the carbamoyloxy)-2-ethyl] piperazine (No. 1l).By reacaeuen of N [v }f )-P 'QPy tion of N-[v-(fiuoroA-benzoyl)-propyl]-N-(hydroxy-2- yy prperazme and methyl rseeyanate. The ethyl) piperazine with cyclohexyl isocyanate. The dihydrohydrochloride was recrystallized from absolute alcohol 50 chloride was recrystallized from 95 alcohol (No. 11

-.[(p y y )l y y (d) N-[w-(fiuoro-4-benzoyl)-propyl]-N-[(isopropyl Y) 2 y piperazine Y F action of carbamoyloxy)-2-ethyl] piperazine (No. l2).- By reac- -[(P Y 2 Y Y Y- l P p tion of N-['y(fluoro-4-benzoyl)-propyl)]-N'-(hydroxy-2- azine and ethyl isoeyanate. The dimaleate was recrystalethyl) piperazine with isopropyl isocyanate. The dimaleliz ed from 95 alcohol. ate was recrystallized from 95 alcohol.

; TABLE 2 t /R, R-'N 1S 0Hr)l-o HO-CO-N R, (or a,)=n

'\ l 1 RI Elementary analysis, percent y 1 Calculated Found o, R f 1 i 1 1: Br R. or R: sen F. o n N c H N 4 t 1 H ZHCI 228 56.65 6.17 7.66 56.85 6.05 7.90

F CO-(CHDa- 5..-. cs. 2 e I 1 E Q 3C4Ht0| 52.10 5.98 8.39 51.99 5.93 8.29

0.; l H -on, 2HCl 182 51.0 6.36 9.90 51.3 6.50 9.10

t F --CO--(CH|)l 7 1 H -C|H| 2HC1 167 51.80 7.36 10.66 52.06 1.20 10.82

(e) N-[(para-fiuorophenoxy) 2 ethyl]-N-[(butyl carbamoyloxy)-2-ethyl] piperazine (No. 13).By reaction of N- (para-fluorophenoxy)-2-ethyl]-N'-(hydroxy-2- ethyl) piperazine with butyl isocyanate. The dimaleate was recrystallized from absolute alcohol.

(f) N-[ (ortho nitrophenoxy)-2-ethyl]-N'-[(butyl carbamoyloxy)-2-ethyl] piperazine (No. 14).By reaction of N-[(ortho-nitrophenoxy) 2 ethyl]-N'-(hydroxy-2- ethyl) piperazine with butyl isocyanate. The product was isolated in the form of its dihydrochloride.

' (g) N-[ (2;4,6-trichlorophenoxy)-2-ethyl] -N'- [pi-phenyl-fl-(butyl-carbamoyloxy)-ethyl] piperazine (No. 15).- By reaction of N-[(2,4,6-trichlorophenoxy)-2-ethyl]-N'- (fl-phenyl-fl-hydroxyethyl) piperazine with butyl isocyanate. The product was isolated in the form of its dimaleate.

(h) N-[(rtho nitrophenoxy) 2 ethyl]-N'-[(allyl carbamoyloxy)-2-ethyl] piperazine (No. l6).By reaction of N-[(ortho-nitrophenoxy) 2 ethyl]-N'-(hydroxy- 2-ethyl) piperazine with allyl isocyanate. The dimaleate was isolated.

(i) N-[(ortho-nitrophenoxy) 2 ethyl]-N'-[(a-naphthyl carbamoyloxy)-2-ethyl] piperazine (No. l7).By reaction of N-[(ortho-nitrophenoxy) 2 ethyl]-N'-(hydroxy-Z-ethyl) piperazine with a-naphthyl isocyanate. The dimaleate was recrystallized from absolute alcohol.

(j) N-(phenoxy-2-ethyl)-N-[ (methyl carbamoyloxy)- 2-ethyl] piperazine (No. 18).-By reaction of N-(phenoxy 2 ethyl)-N'-(hydroxy-2-ethyl) piperazine with methyl isocyanate. The dihydrochloride was recrystallized from absolute alcohol.

(k) N-[ naphthoxy)-et.hyl]-N'-[ (dichloro-3,4-phenyl carbamoyloxy)-2-ethyl] piperazine (No. 19).By reaction of N-[(fl-naphthoxy)-2-ethyl)-N- (hydroxy-Z-ethyl) piperazine with dichloro-3,4-phenyl isocyanate. The product was isolated in the form of its dimaleate.

(l) N-[ (para propionylphenoxy)-2-ethyl]-N'-[ (orthochlorophenyl carbamoyloxy) 2 ethyl] piperazine (No. 20).By reaction of N-[(para-propionylphenoxy)-2-ethyl]-N'-(hydroxy 2 ethyl) piperazine with ortho-chlorophenyl isocyanate. The dimaleate was formed.

(m) N- (para-propionylphenoxy) -2-ethyl] -N'-[ (metachloi'ophenyl carbamoyloxy) 2 ethyl] piperazine (No. 21 ).By reaction of N-[para propionylphenoxy)-2-ethyl]-N'-(hydroxy- 2 ethyl) piperazine with meta-chlorophenyl isocyanate. The product was isolated in the form of its dimaleate.

(n) N (fiuoro-4-benzoyl)-propyl]-N'-[(dichloro- 3,4-phenyl carbamoyloxy)-2-ethyl piperazine (N0. 22).-- By reaction of N-['y-(fluoro-4-benzoyl)-propyl]-N'-(hydroxy-3-propyl) piperazine with dichloro-3,4-phenyl isocyanate. The dimaleate was recrystallized from absolute alcohol.

(o) N (para fiuorophenoxy) 2-ethyl]-N'-[hexyl carbamoyloxy)-2-ethyl piperazine (No. 23).By reaction with N [(para-fluorophenoxy)-2-ethyl]-N'-(hydroxy-Z-ethyl) piperazine with hexyl isocyanate. The

dimaleate was recrystallized from absolute alcohol.

(p) N [(para fiuorophenoxy) 2 ethyl]-N'-[anaphthyl carbamoyloxy)-2-ethyl] piperazine (No. 24).- By reaction of N-[(para-fiuorophenoxy)-2-ethyl]-N'-(hydroxy-2-ethyl) piperazine with a-naphthyl isocyanate. The dihydrochloride was alcohol. I

(q) N [(ortho nitrophenoxy)-2-ethyl]-N-[(parachlorophenyl carbamoyloxy)-2-ethyl] piperazine (No. 25).By reaction of N-[(ortho-nitrophenoxy)-2-ethyl]- N (hydroxy-2-ethyl) piperazine with para-chlorophenyl isocyanate. The dimaleate was recrystallized from absolute alcohol.

(r) N (phenoxy 3 propyl)-N'-(hexyl carbamoyloxy-2-ethyl) piperazine (No. 26).By reaction of N- recrystallized from 95.

[(phenoxy 3 propyl)-N'-(hydroxy-Z-ethyl) piperazine and hexyl isocyanate. The dimaleate was recrystallized from absolute alcohol.

TABLE 3 Elementary analysts, percent Calculated Found Yield, percent Salt R: or R:

112 so. at)

I 58 met (JO-TOE):-

a f-CIHI:

I I I I I I I I I 4. I I I I C) --1 NWT fs. 54 as. '10 .7. 27

11.........'...... Same net-above.

EOIQ.

596a 9255 E EE 36 :3. 2 3 3 3 0 8 3 a: 55 0. 2 mo emoT m 9 EETou Q m 2a 3n 8% to 8 22% m2 65 0 8 No m 2 x; m: v 3 8 o: 8 3 a: 556m 8 Nu m :sfizweam 2 :fiov o O oo mo mo S 2 0 8 2 86 8d 8 3 a: 656m 8 No m 9.. mov o m: S 2 3 5 3 0 3 E 056 g No m i 3 2 8 8 8 8 a: 8 8 m2 mom 8 mo m i cmov o 8d a: 8 8 x; :6 8 8 65 0 8 Q m 02 amov o 8 0 a 8 6 w; 5 0 8 5 m2 5&6 2. mo mo mo m 02 2 s EOTATO S 2 0 :6 8 2 $6 a: 93 m2 056 & mo mov O o :2 nmov o 8i :2 2 2 8 n: 23: 2: 8mm 8 l l m z mov o g m m: 2 5 5 3 8 n: 13 a: QmGN a mo zfiov m i z m o z m o m a s w 2 m x 5 m 5. 22. @qflob Uoufifloib Found Elementary annlysls, percent Calculatcd Yield.

percent. Salt 40 ZCtHtOt 65 2C4H|O| TABLE 3C0n't1nuerl R: or R:

--(CH:) l-CH:

Same as above 12 EXAMPLE IV Dimaleate of N-[ -(fiuoro-4-benzoyl)-propyl]-N-[(paranitrophenyl carbamoyloxy)-2-ethyl] piperazine (No. 28)

10 Into a 250 ml. reaction flask fitted with an agitator, were introduced 11.4 g. (0.0595 mole) of the azide of paranitrobenzoic acid (obtained by the action of sodium nitrite on the acid chloride) and 70 ml. of anhydrous Successive additions of 0.7 g. of triethylene diamine and 8.75 g. (0.0297 mole) of N-[y-(fiuoro-4-benzoyl)- propyl]-N'-(hydroxy-2-ethyl) piperazine, added one drop at a time, were made to 50 ml. of anhydrous benzene. The boiling was continued for a further 4 hours.

After cooling, filtering was carried out in order to eliminate a slight excess of para-nitrophenyl isocyanate. The filtrate was left to allow the carbamate to precipitate in the form of a yellow powder (weight obtained 8.6 g.;

r efiiciency 62%).

The base may be converted into its dimaleate by standard methods.

By operating in a similar manner, the following derivatives were obtained (Table IV).

N-[ (Para-fiuorophenoxy)-2-ethyl]-N-[ (para-nitrophenyl carbamoyloxy)-2-ethyl] piperazine (No. 29)

N -(fluoro-4-benzoyl)-propyl]-N-[ (dirnethoxy-3,4- phenyl carbamoyloxy)-2-ethyl] piperazine (No. 30)

By the reaction of N-['y-(fluoro-4-benzoyl)-propyl]-N- 4O (hydroxy-2-methyl) piperazine on the azide of dimethoxy- 3,4-benzoic acid. The dihydrochloride was recrystallized from a 95 alcohol ether mixture.

N-[- -(fiuoro-4-benzoyl)-propyl]-N'-[para-fiuorophenyl carbamoyloxy)-2-ethyl] piperazine (No. 31)

By reaction of N-['y-(fiuoro-4-benzoyl)-propyl] N'- (hydroxy-Z-ethyl) piperazine on the azide of para-fiuorobenzoic acid. The dihydrochloride was recrystallized from a 95 alcohol ether mixture.

N-[ -(fiuoro-4-benzoyl)-propyl]-N'-[trimethoxy-3,4,5-

phenyl carbamoyloxy)-2-ethyl] piperazine (No. 32)

(hydroxy-Z-ethyl) piperazine on the azide of trimethoxy- 3,4,5-benzoic acid. The dimaleate was recrystallized from 95 alcohol.

N-[y-(Z-thienoyl) propyl]-N'-[(trimethoxy-3,4,5-phcnyl carbamoyloxy)-2-ethyl] piperazine (No. 33)

By action of N-[y-(Z thienoyl) propyl]-N'-(hydroxy 2-ethyl) piperazine on the azide of trimethoyl-3,4,5-benzoic acid. The dimaleate was recrystallized from absolute '.alcohol.

N-[y-fiuoro-4-benzoyl) propyl]-N'-(ortho-fiuoropheny1 carbarnoyloxy)-ethyl piperazine (No. 34)

N-[y-(fiuoroi-benzoyl) propyl] N (para-trifluoromethyl phenyl carbamoyloxy) 2 ethyl] piperazine (N0. 35)

benzene. The resulting mixture was boiled for 1 hour.

13 (hydroxy-Z-ethyl) piperazine on the azide of para-trifiuoromethyl benzoic acid (obtained by the action of sodium nitrite on the acid chloride). The dimaleate was re crystallized in absolute alcohol.

N-[ (trichloro-2,4,6-phenoxy -2-ethyl -N'- (para-nitrophenyl carbamoyloxy)-2-ethyl] piperazine (No. 36)

By the action of N-[ (triehloro-2,4,6-phenoxy)-2-ethyl]- N-(hydroxy-2-ethyl) piperazine on the azide of para-nitrobenzoic acid. The dimaleate was recrystallized from 95 alcohol.

drous benzene was added, in small portions, 0.05 mole (14.7 g.) of N-[' -fiuoro-4 -benzoyl)-propyl]-N-[hydroxy- 2-ethyl] piperazine. The mixture was agitated continuously at ordinary temperature for 1 hour. The precipitate was then collected.

' By operating in an identical manner the following derivatives, listed together in Table V were obtained.

(a) N-[(ortho nitrophenoxy)-2-ethyl]-N-[(para-toluenesulfonyl carbarnoyloxy) 2 ethyl] piperazine (No. 38).-By the reaction of N-[(ortho-nitrophenoxy)-2 ethyl]N"(hydroxy-Z-ethyl) piperazine with para-toluene sulfonyl isocyanate. The dimaleate was also formed.

Rn R-N N-(CHi),,(|3H-OCON\ Rflur 110:8

\ R1 RI Elementary analysis, percent Calculated Found Yield, No. R 11 R1 R101 R: percent Salt. F. C H N C H N F- CO-(CH1):- N

28.....Sameesabove 1 H Sameesabove 80 20.11.0 171 54.0 5.08 8.11 53.56 5.08 &30

29..... 1 H .--..l 38 2HC1 234 49.95 5.35 11.10 49.81 5.50 11.40

F O-(CH:):-

30.--" 1 H OCH: 62 2HCLHH|O 220 54.01 6.30 1.60 54.40 5.60 7.30

F C(J-(CHfir OCH| 31"... Sameasabove-.... 1 H F 80 2HC1 142 54.77 5.76 8.34 54.50 5.70 8.15

32 do 1 H OCH: 55 204E140. 182 55.50 5.71 5.71 55.57 5.91 5.38

l OCH! 33 -.--W 1 H Sameesabove 2C4HOc 153 53.20 5.67 5.81 52.82 5.64 5.76

LB CO-(CHDI 84.. 1 H F 65 2CiH4O| 175 56.10 5.28 6.33 56.23 5.33 6.32

F CQ(CH1):-

Sameasabove 1 H Q0! 70 2C4H4O 178 53.80 4.91 5.80 63.77 5.06 5.54

30,.'..' Cl 1 B G No 204E404 198 46.49 4.14 1.48 46.86 4.13 1.11

Cl-Q-O-(CHM- I Cl EXAMPLE V 65 (b) N-['y-(fluoro-4-benzoyl) propyl]-N-[(chlorosul- N-[v- (fiu0ro-4-benzoyl -propyl -N-[ (para-toluenesulfonyl carbamoyloxy)-2-ethyl] piperazine (N0. 37)

To a cooled and agitated solution of 0.05 mole (9.86 g.) of para-toluenesulfonyl isocyanate in ml. of anhyfonyl carbamoyloxy)-2-ethyl] piperazine (No. 39).-By the action of N-[y-(fiuoro-4-benzoyl) propyl]-N'-(hydroxy-2-ethyl) piperazine and chlorosulfonyl isocyanate.

(c) N [(para fluorophenoxy 2-ethyl]-N'-[(fi-naphthalene sulfonyl carbamoyloxy)-2-ethyl] piperazine (N0. 40) .-By the action of N-[ (para-fiuorophenoxy)2-ethyl]- N-(hydroxy-2-ethyl) piperazine and. fi-naphthalene sulfonyl isoeyanate (obtained by reacting naphthalene with chlorosulfonyl isocyanate). The dimaleate crystallized from isopropanol With a molecule of water.

' I TAB LE R-N N-(CHz)n-*CHOCO-N\ R (or R )=H Elementary analysis, percent I Calculated Found No. R Y 11 R1 R1 or B; Yield, T

I a percent Salt F. C H N C H N F- CO(CH:)1 S07 -CHI I S O; CH

39... -S O)C1 50 180 40.80 5.28 9.04 47.04 5.20 9.80

EXAMPLE v1 Trimaleate of N-[(dimethyl arnino)-2-ethyl]-N'-[(dimethyl carbamoyloxy)-2-ethyl]piperazine (No. 41)

Thefollowing mixture was refluxed for 24 hours:

0.05 mole (10.05 g.) of N-[(dimethylamino)-2-ethyl]-N- (hydroxy-Z-ethyl) piperazine,

0.1 mole (10.76 g.) of dimethyl carbamoyl chloride,

0.2 mole (21.2 g.) of anhydrous sodium carbonate, in

400 ml. of dioxan.

so V 40 2041 1404, Hi0 130 -By operating according to these general conditions the following typical compounds were obtained, the physical characteristics of which are given in Table VI.

(a) N [(dimethylamino) 2 ethyl] N [(dimethyl carbamoyloxy) -2-ethyl] piperazine (N0. 42).By. reaction of N [(dimethylamino) 2 ethyl]-N-(hydroxy-2- ethyl) piperazine with diethyl carbamoyl chloride. The.

trimaleate was recrystallized from alcohol.

(b) N (2 thienoyl) propyl] N [(dimethyl carbamoyloxy)-2-ethyl] piperazine (No. 43).By reaction of N-{7-'(2 thienoyl) propyl]-N'- (hydroxy-2-ethyl) piper-' aziriewith dimethyl carbamoyl chloride. The dihydrochloride was recrystallized from absolute alcohol.

(6) N (B aphthoxy 2 ethyl)-N'-[(dimethyl car-"' bamoyloxy)-2-ethyl] piperazine (No. 44).-By reaction of N- (fl-naphthoxy-Z-ethyl)-N-(hydroxy-2-ethyl) piperazine with dimethyl carbamoyl chloride. The dimaleate was recrystallized from 95 alcohol.

(dimethyl carbamoyloxy) ethyl] piperazine (No. 45).- By reaction of the N-[ -fiuoro-4-benzoyl)-propyl]-N'-[flphenyl-fl-hydroxy ethyl) piperazine with dimethyl carbamoyl chloride. The dirnaleate was recrystallized from absolute alcohol.

TABLE 0 RN N(CHl)n'-CH-OrCo-N\ Elementary analysis, percent;

Calculated Found Yleld, No. R 1: R R =R percent Salt F. C H N C H N 41...). "on, if! ciif 43 3611.0. 182" 48.40 6.45 9.04 48.80 6.61" ass 42..." Sameasabove 1 H C H 20 3C4H0| 186 50.0 6.80 8.65 50.15 6.74 8.01

43..." T I 1 H CH 45 ZHCI 202 47.85 6.33 9.85 47.50 6.30 0.00

k lCO(CH|)| H.. 1 H OH: H 2COH40| 182 57.75 6.13 6.97 58.00 6.10 6.84

I Ha)I- 1 7 EXAMPLE vn Dimaleate of N [7 (fluoro-4-benzoyl)-propyl]-N-[(dibenzyl carbamoyloxy)-2ethyl piperazine (No. 46)

The following mixture was refluxed for a period: 25.35 g. (0.0972 mole) of N-[y-(fiuoro-4-benzoyl)-propyl]-N'- (hydroxy-2-ethyl) piperazine, 12.6 g. (0.0486 mole) of dibenzyl carbamoyl chloride (obtained by the action of phosgene on dibenzylarnine in toluene) and 90 ml. of xylene.

After cooling, water was added to the solution in order to dissolve the amino-alcohol hydrochloride. The water was decanted, and the organic phase was separated and dried over Na SO After evaporation of the solvent under reduced pressure, a residue was obtained which was converted to the dimaleate in standard fashion. H

In similar manner the typical compounds listed in Table VII were prepared.

(a) N [(para-acetyl phenoxy)-2ethyl]-N-[dibcnzyl carbamoyloxy)-2-ethyl] piperazine (No. 47).--By reaction of N-[(Para-acetyl phenoxy-Z-ethyl]-N'-(hydroxy-2- ethyl) piperazine with dibenzyl carbamoyl chloride.The dimaleate was formed.

(b) N [(dimethylamino) -.2 ethyl]-N'-[(diphenyl carbamoyloxy) 2 ethyl] piperazine (No. 48).-By reaction of the N-[(dimethylamino-Z-ethyl]-N-(hydroxy- Z-ethyl) piperazine with diphenyl carbamoyl chloride in toluene. The trimaleate was recrystallized from 95 alcohol.

=(c) N-[v (fiuoro 4 benzoyl)-propyl]-N'-[ (tetramethylene carbamoyloxy) 2 ethyl] piperazine (No. 49) By reaction of the N-[ -(fiuoro-4-benzoyl) propyl]- N (hydroxy2-ethyl)piperazine with chloroformyl pyrrolidine in toluene (product of the condensation of pyrrolidine and phosgene in toluene). The product was iso lated in the form of its dimaleate.

(d) N [-y (fluoro 4 benzoyl)-propyl] N [(N- cyclohexyl N (ethyl carbamoyloxy) 2 ethyl] piperazine (No. 50). By reaction of N-[y-(fluorot-bcnzoynpropyl]-N'-(hydroxy-2-ethyl) piperazine with N-cyclohexyl-N-ethyl carbamoyloxy chloride (product of condensation of N-cyclohexyl-N-ethylamine and phosgene in toluene). The dihydrochloride was recrystallized from an absolute alcohol ether mixture.

(e) N ['y (fiuoro 4 benzoyl)-propyl]-N'-[(diphenyl carbamoyloxy)-2-ethyl] piperazine (No. 3l).- By reaction of the N-[ -(fiuoro-4 benzoyl)-propyl]-N'- (hydroxy 2 ethyl) piperazine with diphenyl carbamoyl chloride. The dimaleate was recrystallized three times from absolute alcohol.

(f) N [(Para fiuorophenoxy) 2 ethyl]-N'-[(tetramethylene carbamoyloxy) 2 ethyl] piperazine (N0. 52).By reaction of N-[(para-fiuorophenoxy)-2ethyl]- N (hydroxy 2 ethyl) piperazine with chloroformyl pyrrolidine. The dimaleate was prepared then recrystallized from absolute alcohol.

TABLE 7 RN N-(CHz) r-C HO-C ON\ [n=l;R1=H] Elementary analysis, percent Calculated Found No. R R: R; Yield, Salt F. C H N C H N percent F- CO(CHz)r CH CH 47... Sameasabove Sameasabova-.. 50 2C|H(0l 158 62.55 6.03 5.62 62.33 6.08 5.37

CH CO 'O-(CHfir 48.-. CH; Q Q 73 30411404 170 56.50 5.92 7.53 56.79 6.10 7.22

Hr- H:

50--- Sameasabove C:H| 77 21101 165 57.68 7.69 8.08 57.41 7.73 7.88

51 do Q 50 2041104 146 61.50 5.55 5.82 61.27 5.77 6.10

CHz-CH: 30 2CH404 54.35 6.03 7.04 54.44 6.07 6.81

CHr-CH:

1 9 EXAMPLE VIII The neuroleptic activity of the compounds prepared as described above was investigated by two tests: the first consisted of measuring the motivity of the mouse, the second was based on the potentialization of barbituric narcosis.

-(1) Study of motivity The method used was that described by Dews, P. B., in J. Pharmacol. 1953, 8, 46-48 and by Boissier, I. R., and Simon, P., in Arch. Int. Pharmacodyn, 1955, 158, 212."

Isolated mice were placed in cages across which crossed pencils of rays were passed to fall on photoelectric cells.

Actimeters made it possible to count the number of light rays traversed by the animal in 10 minutes.

The medicament to be tested an dthe reference product (chloropromazine: mg./kg.) were administered per os 30 minutes before the test.

The results are shown in Table 8.

TABLE 8.AC'IION ON MOTIVIIY Acute toxic- Percentage of activity Under the same experimental conditions chlorpromazine at 5 mg./kg. p.o. gives 60% activity in relation to the sample.

Examination of these results indicates that derivatives according to the invention numbered 18, 27, 30,34 and 43 have remarkable sedative properties. In fact motivity of the animals is clearly diminished with doses of less than 1A60 0f the D5014- EXAMPLE IX (2) Test of potentialization of the narcosis The method of operation was that described by Winter, C. A., J. Pharmacol. Exp. Ther. 94, 7-11, 1948.

The investigation was to see whether the preliminary administration, by gastric probe, of the experimental prod- I not extended the period of sleep induced by injecting mebubarbital.

The results are shown in Table 9.

TABLE 9.ACTION 0N POTENTIALIZATION 0F SLEEP Percentage of extension Acute of time of sleep toxicity, 1) 0 mouse, Doses p.o.,

rng./kg mg./kg. Percent Compound No.:

Under the same experimental conditions chlorpromazine 20 EXAMPLE x- Analgesic activity The Siegmund test was used to prove the analgesic activity. See Siegmund, Cadmus: Proc. soc. exp. biol. med. 1957, 95, 729; .The intra-peritoneal injections of phenylbenzioquinone provokes in the mouse crises whose frequency is diminished by the preventive administration of analgesic. The substances were administered-orally 30 minutes before the injection of the algogenic agent.

The animals were observed from the 5th to the 10th minute afterinjection of phenylbenzoquinone. The percentage of animals protected was calculated. A mouse is considered to be protected if --it executes less than 5 stretches in 5 minutes.

The results are given in Table 10;

TABLE 10 Percentage of protection in Acute relation to samples toxicity, p.o. mouse, Doses .o. -mg./kg. mg. Percent 600 10/20 50/60 5 v 400 2 30 g 50 80 750 i 25 5o EXAMPLE XI Than'ti-infla'riiinatory activity ilie compounds of the invention was investigated using the oedema test with c'arragenin described by Winter, C. A., Risley, E. A., and colleagues; Proc. soc. exp. biol. New York, 111, 544 (1962).

' 'A' rat receivedarrinjection in the/plantar. arch of 0.05

at 4 mg./kg. per 0s prolongs the duration of the sleeping time by at least 100%.

Derivatives 18, 27, 30 and 31 potentialize to a very large degree barbiturate narcosis. The doses administered were in fact very small in relation to their general toxicity.

Using the results of these tests (Examples VIII and IX) as a basis it can be stated that the derivatives of the invention numbered 18, 27 and 30 possess remarkable neuroleptic qualities.

mole of a solution with 1% carragenin in physiological serum.

The volume of the front paw was measured immediately andagain three'liours after the injection of the pholgogenie agentfwith mean of the Apelab plethysmorgraph.

The substance was administered orally one hour before the injection of the carragenin.

The results are given in Table 11.

In the same experimental conditions, phenylbutazone mg./kg. causes 50% inhibition of the experimental oedema.

Derivative No. 28 shows an anti-inflammatory activity whose extent is worth noting.

' EXAMPLE XII The anti-pyretic activity of Compound 43 was investigated by following the procedure laid down by Smith, P. K., -and Hambouger, W. 1., in J. Pharmacol. Exp. Ther. 54, 346 (1935).

A hyperthermia was provoked experimentally in the rat by injecting beer yeast the day before the experiment.

All products were administered, per os, 16 hours after the injection of the pyrogene.

Compound No. 43--DL close to 750 mg./kg. p.o. possesses at a dosage of 100 mg/kg. an antipyretic activity scarcely less than that obtained by using pyramidon at a dosage of 125 mg./l:g. p.o.

EXAMPLE XIII Action on arterial pressure TABLE 12 Percentage of hypoten- Acute sion in relation to toxicity, acetyl-choline mouse p.o., Doses IV mgJkg. mgJkg. Percent Compound No.:

The compounds mentioned in the above table cause hypotension comparable to that obtained by acetylchlorine at 1 mcg./kg. However, to obtain an elfect similar to the sample it was necessary to operate with larger doses.

In addition it may be noted that certain compounds (9, 12, 18, 30) represent, at doses lacking any action per se, adrenolytic activity of some interest which is generally encountered in the family of neuroleptics.

EXAMPLE XIV Anti-histamine activity To investigate this activity two tests were used:

protection in connection with bronchospasm involving histamine in the guinea-pig;

inhibition of the effects of the histamine on the ileum of the guinea-pig.

(1) Bronchospasm.-The procedure followed was that described by Halpern, B. N., in Arch. Int. pharmacodyn. 1942. 68, 339.

Administration of histamine to the guinea-pig (250- 300 g.) in the form of an aerosol produced a bronehospasm in a period from 30 to 90 seconds and a coma in 3 or 4 minutes.

Administration of an anti-histamine product 30 minutes before the aerosol delays the appearance of the bronchospasm (period in excess of 5 minutes).

The results are shown in Table 13.

TABLE 13 Percentage of Acute protection toxicity p.o. mouse, Doses p.o.,

rug/kg. rug/kg. Percent Compound No.: 20 80 12 450 40 100 31 400 20 40 In the same experimental conditions mepyramine, at a dosage of 20 mg/kg. per os, completely protects guinea-pigs (protection index 100%).

22 EXAMPLE XV Anti-histamine activity (2) Isolated ileum of guinea-pig.--The procedure was as described by R. Magnus, Arch. Anat. Physiol. Lps. 1904, 102, 123 and 349.

Principle:

Research into the action per se and antagonism in relation to contracturant effects caused by histamine on the isolated ileum of the guinea-pig, kept alive in a bath of Tyrode liquid at 37 C., aerated and atropined.

Movements were recorded in accordance with Magnus method.

Results:

Compounds 7, 9 and 18 showed. a certain antihistamine activity but it was necessary to give doses times greater than that of mepyramine to have the same effect.

Conclusion:

Several derivatives of this invention indicate an antihistamine activity which is far from being insignificant.

These interesting properties of the derivatives of the invention and of their salts make them useful therapeutic medicaments in the treatment of various diseases of the nervous system, such as psychosomatic affective neuroses, manifestations of anxiety in its various forms, insomnia, the treatment of painful syndromes of 'various origins, in diseases of anti-inflammatory character, and also in certain cases of hypertension.

EXAMPLE XVI Tablets of the following composition were prepared: For one tablet:

Daily dosage is 3 to 4 tablets of the above composition. EXAMPLE XVIll Therapeutic use may be made of capsules having the following composition:

For one capsule: Compound No. 18, 0.010 g.

Daily dosage is 1 to 6 capsules of the above composition. EXAMPLE XVIII Therapeutic application by way of the rectum of suppositories of the following composition:

For one suppository:

G. Compound No. 27 0.050 ExcipientQ.s.p., 3 g.

The suppository is administered at night before retiring.

I claim:

1. A compound of the group consisting of N-[y-(Z-thienoyl)propyl] N [(dimethylcarbamoyloxy)-2-ethyl] piperazine and its acid addition salts.

2. An acid addition salt in accordance with claim 1 wherein the acid is selected from the group consisting of hydrochloric acid and maleic acid.

References Cited UNITED STATES PATENTS 3,189,600 6/1965 Huebner 260-268 FT 2,836,595 5/1958 Parcell 260268 PH 2,979,507 4/1961 Janssen 260-268 FT 2,985,657 5/1961 Janssen 260-268 FT 3,138,597 6/1964 Schut 260268 PH 3,719,680 3/1973 Abbate 260-268 PH DONALD G. DAUS, Primary Examiner US. Cl. X.R.

260'l47.2 B, 268 R, 268 H, 268 BC; 424248, 250

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent NO. 308101897 Dated May 14, 1974 Inventor) Q Jean B. Philippe It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, in the formula at the third line from the bottom,

"R" should be -R Column 3, lines 32-8, "halophenyl" should be -halogenophenyl-; Colunm 5, line 26, Y -fluoro" should be Y (fluoro-; Column 5, line 41, "N- [dimethylamino" should be N- (dimethylamino-;

Column 7, line 44, "N- [para" should be -N- (Para-;

Column 8, in the heading over Table 3,

should be /1 Column 9, under the heading "N" in Item 13, .7.0l"

should be -7.0l;

Column 12, line 71, "N'- (para" should be -N' (para--; Column 13, line 5, "N (para" should be --N' (para-; Column 18, line 19, "No. 31" should be --No 5l-;

Column 19, line 16, "an dthe" should be -and the;

Column 19, line 44, "D should be --DL 50--;

Column 19, line 66, "c or-promazine" should be -chlo:ropromazine-- Column 20, line 50, "pholgogenic" should be -phlogogenic--; Column 20, line 51, "Apelabplethysmorgrapw' should be -APELAB plethysmograph-;

Column 20, line 59, "p.p." should be -po--.

Signed and sealed this 1st day of October 1974.

(SEAL) Attest:

MCCOY M. GIBSON JR. 4 C. MARSHALL DANN Attesting Officer Commissioner of Patents 

